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Genetic analysis on familial nonsyndromic hearing loss using next-generation sequencing

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Authors
박기범
Advisor
김종일
Major
의과대학 의과학과
Issue Date
2014-02
Publisher
서울대학교 대학원
Keywords
Hearing lossnext-generation sequencingwhole exome sequencingtargeted re-sequencing
Description
학위논문 (박사)-- 서울대학교 대학원 : 의과학과, 2014. 2. 김종일.
Abstract
Introduction: Hearing loss is a common sensorineural disorder and half of hearing loss is derived from genetic causes. Due to complexity of hearing mechanism, about 50 genes have been found to have genetic aberrations from previous studies. Next-generation sequencing (NGS) using massively parallel sequencing of DNA is a technology for detection of genetic information and variations from large datasets. I could apply several analytical methods from this platform to pinpoint the causal variations of hearing loss.
Methods: Two independent approaches were used for different familial nonsyndromic hearing loss cases. Whole exome sequencing (WES) for one large family and targeted re-sequencing (TES) for a group of probands of hearing loss were used, respectively. WES was performed with four patients and four normal members in the family and multiphasic analysis was conducted upon copy number variation(CNV), linkage analysis and single nucleotide variation (SNV) calling. TES was performed with 20 probands after pre-screening and I filtered the candidate variants from TES by the multistep criteria to elucidate the possibly causal variants.
Results: In WES study, there were no candidate CNVs that co-segregated with the disease. I detected six regions that had LOD score > 1 from linkage analysis and one SNV in gamma-actin 1 (ACTG1) was a novel mutation. ACTG1 was a known causal gene of hearing loss and the mutation site was predicted to interact with ATP. In TES study, 32 cases were originally collected. Due to failure of pre-screening genetic analysis, 20 cases were analyzed by TES with SNV and indel in the targeted genes. I filtered the candidate variants by multi-steps with inheritance pattern of the gene, Sanger sequencing of the case, the control and/or the family members and clinical features. 13 of 20 cases had final candidate variations and 25 of total 32 cases had candidate variations in sum.
Conclusions: Trial for potential therapeutics and genetic counseling can be considered, if precise genetic diagnosis for hearing loss is possible. Especially, with analysis of NGS technology, the genetic diagnosis of hearing loss could be more accessible and efficient.

* This work is published in “Multiphasic analysis of whole exome sequencing data identifies a novel mutation of ACTG1 in a nonsyndromic hearing loss family. BMC Genomics. 2013 Mar 18
14:191” and “Diagnostic application of targeted resequencing for familial nonsyndromic hearing loss. PLoS One. 2013 Aug 22
8(8):e68692.”
Language
English
URI
http://hdl.handle.net/10371/122258
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College of Medicine/School of Medicine (의과대학/대학원)Dept. of Biomedical Sciences (대학원 의과학과)Theses (Ph.D. / Sc.D._의과학과)
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